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La phosphatase CDC25A et le micro-ARN-16 au coeur de la biologie des leucémies aiguës myéloïdes portant une mutation FLT3-ITD

Abstract : Patients presenting an Internal Tandem Duplication in the FLT3 receptor (FLT3-ITD) represent up to 25% of Acute Myeloid Leukemia (AML) cases, and suffer from an overall poorer outcome than their peers expressing the wild type receptor. Our team has demonstrated that expression of the cell cycle regulator CDC25A is tightly controlled by FLT3-ITD in this model, and that CDC25A is a key player in the biology of these AML. However, targeting CDC25A has proven complicated and currently available pharmacological inhibitors show high toxicity. Therefore we are studying the regulation mechanisms of CDC25A downstream of FLT3-ITD, to hopefully identify another strategy to target this pathway. In this work we first show that in FLT3-ITD AML, STAT5 is a direct transcriptional regulator of CDC25A. Furthermore, we identify the micro-RNA-16 (miR-16) as a negative regulator of CDC25A whose expression is repressed by STAT5 downstream of FLT3-ITD. Interestingly, FLT3-ITD leukemic cells are very dependent on the repression of miR-16 expression for their proliferation and differentiation block, two hallmarks of AML. We also highlight a very high sensitivity to the inhibition of Bcl2, another known miR-16 target, in FLT3-ITD cell lines and AML primary samples, compared to the FLT3-WT ones.
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Gabrielle Sueur. La phosphatase CDC25A et le micro-ARN-16 au coeur de la biologie des leucémies aiguës myéloïdes portant une mutation FLT3-ITD. Cancer. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30156⟩. ⟨tel-02879095⟩

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